tbuckley/cabot-search huggingface dataset:
P1567: STUDY OF THE ASSOCIATION OF I-FGF23 PEPTIDE WITH MARKERS OF IRON HOMEOSTASIS, ERYTHROPOIESIS, INFLAMMATION AND BONE METABOLISM IN PEDIATRIC PATIENTS WITH ACUTE INFECTION
Authors: Eleni Papastergiou, Dimitrios Rallis, Afroditi Papagianni, Vasileios Cholevas, Ekaterini Siomou, Eftychia Steiakaki, Alexandros Makis
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Functional iron deficiency (FID) and anemia occur frequently during inflammation and can exacerbate the clinical course of patients. Hepcidin, a peptide hormone produced by hepatocytes, is the master regulator of iron homeostasis, by inducing hypoferremia. Intact-Fibroblast Growth Factor 23 (i-FGF23), is a primarily phosphaturic hormone, produced mainly by bone, that regulates mineral metabolism. It has been demonstrated that low concentrations of i-FGF23 may increase hepcidin expression resulting in FID during acute inflammation but only on experimental level, whereas this peptide has been extensively studied on clinical grounds in chronic inflammation, especially chronic kidney disease Aims: The aim of this prospective clinical study is to evaluate the associations of i-FGF23 with markers of iron homeostasis, erythropoiesis, inflammation and bone metabolism in pediatric patients with acute infections and no comorbidity. Methods: Seventy-nine children, aged 1 month – 13 years, 42 males - 37 females, participated in the study. Children with diseases and nutrient deficiencies causing anemia were excluded from the study. Twenty-six patients had bacterial infections, 26 had viral infections and 27 children were healthy controls. Complete blood count, markers of inflammation, iron and bone metabolism, serum hepcidin and i-FGF23 were compared between the groups. Results: Thirty-nine % of patients with bacterial infection, 12% of patients with viral infection and 0% of controls presented characteristics of anemia of inflammation (p<0.001). Ninety-two % of patients with bacterial infection and 81% of patients with viral infection had FID (p<0.001). I-FGF23 was significantly positively correlated with iron metabolism parameters and negatively with duration of fever, markers of inflammation and hepcidin. Hepcidin was significantly positively correlated with duration of fever, markers of inflammation and negatively with iron, bone metabolism parameters and i-FGF23. I-FGF23 and hepcidin were not interrelated in linear regession analysis, after adjusting for the infection status and CRP, whereas the absence of infection was the only factor strongly correlated with i-FGF23 [standardized coefficient 11.45, 95% CI (1.97, 20.93), p=0.019]. Summary/Conclusion: The inflammatory process during acute infections in children decreases i-FGF23, leading to an inverse interrelationship of i-FGF23 with the increased hepcidin and to reduced bone metabolism markers. Further research will elucidate the interaction between FGF23 and hepcidin and the effect on anemia of inflammation in conjunction with bone microenvironment changes. Keywords: Inflammation, Infection, Pediatric, Anemia
P1331: DISTINCT REACTIVITY TO ENVIRONMENTAL FACTORS OF YS VERSUS HSC DERIVED PROGENITORS DICTATE HEMATOPOIESIS IN THE MOUSE FETAL LIVER
Authors: Francisca Soares-Da-Silva, Marcia Peixoto, Valentin Bonnet, Gustave Ronteix, Marie-Pierre Mailhe, Charles Baroud, Perpétua Pinto-Do-Ó, Ana Cumano
Journal: HemaSphere (2023)

Topic: 23. Hematopoiesis, stem cells and microenvironment Background: During embryogenesis, the hematopoietic system is formed by waves of progenitors that arise from the yolk sac (YS) and dorsal aorta (DA). These waves converge to the fetal liver (FL), where they display distinct dynamics of proliferation and differentiation. New evidence by ourselves and others show that YS, but not hematopoietic stem cell (HSC)-derived progenitors, drives hematopoiesis during the fetal period. Aims: Our aim is to identify how these two progenitor types respond to environmental cues to understand embryonic hematopoiesis. Methods: We evaluated the FL stromal compartment by spectral flow cytometry and single-cell gene expression, from mid-to-late gestation. We performed 3D immunofluorescence of the FL to identify the different stromal and hematopoietic populations and developed a cell-segmentation pipeline to extract single-cell positions and perform neighborhood analysis, resulting in a network representation of the FL. For the localization of cytokine expressing cells we used Kitl- and Cxcl12-reporter mice. Results: Here, we analyzed the FL microenvironment and found that at early stages both YS and DA-derived progenitors accumulate at the periphery of the FL where Kitl is mainly produced by mesothelial cells and hepatoblasts. Also, whereas certain hematopoietic cytokines (Csf1, Tpo and Kitl) are expressed by multiple cell types, Epo and Il7 are exclusively expressed by hepatoblasts, suggesting a critical role for these cells. Cytokine levels increase from E12 to E14 and decrease thereafter, indicating that the microenvironment is most supportive for hematopoiesis at earlier stages. At E14, while YS-derived progenitors remain concentrated at the periphery, DA-derived progenitors spread throughout the parenchyma in response to increased Cxcl12 levels in perivascular cells, compatible with their later migration to the bone marrow. Summary/Conclusion: Overall, we identified a new component of the FL microenvironment: the mesothelium and the periphery region. We hypothesize that low cytokine levels accommodate both the differentiation of YS-progenitors and the expansion of the HSC compartment due to their distinct sensitivity to environmental cues. Keywords: Fetal, Hematopoietic stem and progenitor cells, Hematopoietic microenvironment
PB1920: TARGETING THE TUMOR MICROENVIRONMENT INTERACTIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING LEUKOTRIENE INHIBITORS
Authors: Laia Sadeghi, Magali Merrien, Magnus Bjorkholm, Birgitta Sander, Hans-Erik Claesson, Anthony Wright
Journal: HemaSphere (2023)

Topic: 7. Chronic myeloid leukemia - Biology & Translational Research Background: Chronic Lymphocytic Leukemia (CLL) is one of the most frequent types of leukemia in the west, including the Nordic countries. CLL cells proliferate and survive in microenvironment niches where they receive growth and survival signals. Adhesion of tumor cells to stromal cells in such niches stimulates the activation of multiple singling pathways, including B-cell receptor (BCR) signaling which is required for tumor cell survival. Recently, irreversible BTK inhibitors, ibrutinib, acalabrutinib and zanubrutinib have been proven to inhibit malignant B-cell survival through hindering tumor-microenvironment interactions. However, despite this progress, response to treatment with BTK inhibitors, is inadequate in some patients and patients frequently develop resistance to treatment. This is in part due to the fact that CLL is a heterogenous disease where tumor cells utilize different strategies for migration and adhesion. Therefore, studies are required to identify multiple therapeutic targets to disrupt tumor-microenvironment interactions. Aims: 5-lipoxygenase (5-LOX) catalyzes the conversion of arachidonic acid to leukotrienes (LTs). We showed that inhibition of 5-LOX decreased adhesion of Mantle cell lymphoma (MCL) cells to the stromal cells. Here in this study, we seek to explore the role of 5-LOX pathway in tumor-microenvironment interaction in CLL. Methods: An established ex vivo co-culture model system mimicking tumor-microenvironment interactions seen in vivo used to study the adhesion of CLL cells to stromal cells in the presence of several 5-LOX inhibitors. Results: We showed that adhesion of CLL cells is reduced by 5-LOX inhibition in a group of CLL patients. Cluster analysis identified distinct groups of patients with different patterns of response to 5-LOX inhibitors demonstrating that mutation burden and microenvironment context may influence response to these inhibitors. Summary/Conclusion: Our results suggest that 5-LOX has potential as a putative novel therapeutic target for development of new strategies for treatment of CLL. Keywords: B cell chronic lymphocytic leukemia, Chronic lymphocytic leukemia
PB1946: NOTCH PATHWAY MUTATION CONTRIBUTES TO INFERIOR PROGNOSIS IN HBV-INFECTED CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Chunyu Shang, Yue LI, Jinhua Liang, Jia-Zhu Wu, Huayuan Zhu, LI Wang, Jianyong LI, Wei Xu
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. Aims: In order to investigate the relation between NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV positive CLL patients and 244 HBV-negative CLL. Methods: A total of 342 treatment naïve patients diagnosed with CLL at the First Affiliated Hospital of Nanjing Medical University from 01 Jan 2010 to 31 Oct 2021 were enrolled in our study. The mutation hotspots of NOTCH pathway genes were analyzed by Next Generation Sequencing (NGS) of DNA that used PCR for the identification of genomic mutation. Fisher exact and χ2 tests were used to assess the correlation between HBV infection and clinical, demographic factors in CLL patients. Survival curves were generated by Graphpad 9.5. Results: NOTCH mutations were more frequent in HBV positive CLL subgroup (17.3% vs 7.4%, p=0.033). By survival analysis, HBV infection was associated with disease progression and poor survival [p=0.0099 for overall survival (OS) and p=0.0446 for time-to-treatment (TTT)]. Any lesions of the NOTCH pathway (NOTCH1, NOTCH2 and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p=0.016 for OS and p=0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV negative patients (p=0.1706 for OS and p=0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. Summary/Conclusion: In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of NOTCH signaling pathway might play a crucial role.Keywords: Chronic lymphocytic leukemia, Prognosis, Notch signaling, Hepatitis B virus
P1495: A PHASE III, RANDOMISED CONTROLLED SAFETY, EFFICACY AND COST EFFECTIVENESS TRIAL OF INTRAVENOUS IRON ISOMALTOSIDE (I3R) AND FERRIC CARBOXY MALTOSE (FERIUMR) IN SUBJECTS WITH IRON DEFICIENCY ANEMIA
Authors: P Harikrishnan, Uday Yanamandra, J Muthukrishnan, Deeptika Aggarwal, Arun Yadav, Sk Singh, Harshit Khurana, Renjith Verghese
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Anemia is a significant public health problem in India, more prevalent in pregnant women and young children. Oral iron is the first-line therapy for IDA in resource constraint settings because of its low cost, perceived safety profile, and ease of administration. Nonetheless, the oral iron absorption is affected by several dietary factors, particularly high phytate content in the Indian diet. Also, the high incidence of gastrointestinal side effects leads to poor compliance to oral Iron therapy which further leads to suboptimal responses. Parenteral iron therapy on the other hand, leads to rapid replenishment of iron stores. The choice of parenteral iron formulation is unclear owing to lack of head-to-head clinical trials in real world resource constraint settings. Aims: To compare the efficacy and safety of intravenous iron isomaltoside (i3R) and Ferric Carboxy Maltose (FeriumR) in subjects with iron deficiency anemia. Methods: This is a randomised single institutional clinical trial, with 1:1 randomisation. The study was registered with CTRI vide CTRI/2023/1/048725 and universal trial number U1111-1286-2021. The study was conducted in a tertiary care center of South India. It is a single blind study wherein study population were blinded to the study arm. Single infusion of 1000 mg i3R (ARM-A) or FCM (ARM-B) were administered after establishing IDA (based on serum ferritin, iron, TIBC and percentage saturation). Currently we are presenting the results of pre-planned interim analysis after achieving 25% follow-up at 4weeks of randomisation. All adverse event were recorded using Likert scale daily for 1 week after the intervention and thereafter at 4, 8 and 24 weeks. Patients were further planned to be followed up at 4, 8, and 24 weeks for increase in Hb and ferritin levels. Results: As part of interim analysis, at 4 weeks of randomization, 77 and 40 were allocated to ARMs A and B respectively. The mean baseline demographic characteristics (age, gender distribution, baseline Hb and Ferritin values) were comparable in both the arms with statistically significant difference. After intervention, a mean increase of 3.1g/dL and 3.64 g/dL of Hb was noted in ARM-A and ARM-B respectively with no Summary/Conclusion: The interim analysis of this safety and efficacy comparison trial has noted no statistically significant difference between the two parenteral preparations.Keywords: Anemia, Iron deficiency anemia
P1009: SKLB054, A NOVEL JAK2 INHIBITOR, POTENTLY TREATS MYELOPROLIFERATIVE NEOPLASM WITH JAK2V617F MUTATION
Authors: Ailin Zhao, Tao Yang, Linyu Yang, Mengshi Hu, Xin Wang, Jinjin Wang, Meng LI, LI Wang, Jinbing Zhu, Lijuan Chen, Ting Niu
Journal: HemaSphere (2023)

Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background:JAK2V617F mutation plays a driver pathogenic role in myeloproliferative neoplasms (MPNs), including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. However, the approved JAK2 inhibitors, ruxolitinib and fedratinib, have been proved to cause hematologic toxicities and Wernick’s encephalopathy. Aims: This study aims to develop a novel JAK2 inhibitor, SKLB054, and investigate the effects of treating MPNs in vitro and in vivo. Methods:In vitro kinase assay was conducted to evaluate inhibition of JAK family by SKLB054 and molecular docking study was performed to explore whether SKLB054 bound to JAK2 protein. Proliferation, cell cycle, and apoptosis of JAK2V617F-dependent cells were examined to assess in vitro effect of SKLB054. Western blot was performed to explore the effect of SKLB054 on critical proteins in JAK/STAT and other signaling pathways. An erythroleukemia xenograft model and a JAK2V617F-induced MPN mouse model were established to evaluate the anti-tumor efficacy of SKLB054 in vivo. Results: SKLB054 was a novel JAK2 inhibitor, inhibiting JAK2 with an IC50 of 3 nM. It inhibited proliferation of various cell lines, induced G2/M cell cycle arrest, and promoted apoptosis of JAK2V617F-dependent cell lines. Moreover, SKLB054 suppressed phosphorylation of JAK2, STAT3, STAT5, and ERK in JAK-STAT pathway. In vivo, SKLB054 significantly inhibited tumor growth in an erythroleukemia xenograft model. Notably, in JAK2V617F-induced MPN murine model, SKLB054 markedly reduced hepatosplenomegaly and prolonged survival without obvious toxicity, which was better than ruxolitinib (Figure 1). In addition, SKLB054 also suppressed JAK-STAT signaling pathway in vivo.Figure 1. SKLB054 significantly attenuated splenomegaly of JAK2V617F-induced MPN mice. Summary/Conclusion: SKLB054, a potent JAK2 inhibitor, exhibited a promising therapeutic effect on MPNs. Keywords: Janus Kinase inhibitor, Myelofibrosis, Myeloproliferative disorder
P1636: ACUTE PRESENTATIONS OF ORAL ANTITHROMBOTIC ASSOCIATED HAEMATHROSIS IN AN URBAN TERTIARY REFERRAL CENTRE
Authors: Marissa Swanepoel, Nicholas Meyer, Sher Tio Worthy, Sean Garvey, Aoife Delaney, Virginia Silvari, Catriona O’leary, Paul Macmullen, Maeve Crowley
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Direct Oral Anticoagulant (DOAC) use is increasing with their favourable safety profile and ease of administration. Haemarthrosis is a potentially devastating complication of anticoagulation and the natural history of DOAC associated haemarthrosis is poorly described. Aims: We aimed to better define the epidemiology, diagnosis and natural history of DOAC associated haemarthrosis in an urban Irish population Methods: Retrospective chart review review of all presentations of monoarticular arthritis to a tertiary referral hospital in Ireland over a two-year period. Results: 38 patients were identified with an isolated monoarticular arthritis. 11 (29%) of patients were found to have a haemarthrosis with the remaining 27 patients diagnosed with either crystal arthropathies (gout, pseudogout) or septic arthritis. Of the haemarthroses, 7 patients were diagnosed via joint aspirate and 4 by imaging studies alone. All patients with haemarthroses were on antithrombotic therapy at presentation. 7 patients were taking a DOAC, 3 patients on warfarin and 1 patient on aspirin alone. 10 patients were anticoagulated for atrial fibrillation and one for a history of ischaemic heart disease. Patients were predominantly older (mean age 85, Range 76-94) and male (8 male vs 3 female). Most (8/11) haemarthroses were spontaneous with only 2 associated with minor trauma and one with major trauma. Renal function was normal in 9/11 patients with one mild and one moderate AKI. No patients had underlying CKD. All patients were managed conservatively with physiotherapy and cessation of anticoagulation. Two patients required bracing. One patient died of hospital acquired pneumonia during admission and a second patient was found to have no current indication for ongoing anticoagulation. In all other patients antithrombotic therapy was reinstituted no patient was readmitted with further joint bleeding Summary/Conclusion: Haemarthrosis represents a significant percentage of acute presentations of isolated monoarthritis. Most are spontaneous and all occurred in patients on antithrombotic therapy. Fewer patients than expected had risk factors that would be associated with DOAC induced bleeding (dual antithrombotic therapy, significant renal dysfunction). All bleeds were managed conservatively and antithrombotics recommenced without readmission for further bleeds. Our findings are similar to a recently published study from the United Kingdom (Dalrymple et. al.) suggesting that anithrombotic therapy can be safely reinstituted in these patients and the general outcome is favourable. Keywords: Antithrombotic therapy, Anticoagulation, Bleeding
S108: ATP CITRATE LYASE IS AN ESSENTIAL PLAYER OF THE METABOLIC REWIRING INDUCED BY PTEN LOSS DURING T-ALL DEVELOPMENT
Authors: Guillaume Andrieu, Guillaume Andrieu, Estelle Balduci, Caroline Costa, Els Verhoeyen, Ivan Nemazanyy, Ganna Pannasiuk, Kathryn Wellen, Elizabeth Macintyre, Vahid Asnafi, Melania Tesio
Journal: HemaSphere (2023)

Background: Alterations inactivating the tumor suppressor gene PTEN drive the development of distinct human pathologies, including solid and hematological cancers. In T-cell acute lymphoblastic leukemia (T-ALL), PTEN loss is commonly observed and it defines a subset of poor-prognosis patients. Aims: In order to face the unmet clinical challenge for these PTEN-null cases, we investigated the metabolic rewiring induced by PTEN loss in T-ALL with the aim to identify novel metabolic vulnerabilities. Methods: By combining murine models to genetic, transcriptomic and metabolomic profiling of primary patient cells, we identified the crucial role of the enzyme ATP citrate lyase (ACLY). Results: We showed that the enzyme ATP citrate lyase is strictly required for the transformation of thymic immature progenitor cells as well as for the growth of established human T-ALL cells, which remain dependent on ACLY activity even upon transformation. Using a PTEN-deficient mouse model, we first demonstrated that whereas PTEN mutant mice all died within 17 weeks, the concomitant ACLY deletion prevented disease initiation in 70% of the animals, which did not show any signs of disease development over a 1-year follow-up. Mechanistically, we show ACLY regulates BCL-2 expression thereby preventing the apoptosis of pre-malignant DP thymocytes, which are the cell of origin of the disease in our model. The further genetic, transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells selectively activate ACLY and are specifically sensitive to its genetic targeting both in vitro and in vivo. Summary/Conclusion: Showing that ACLY is crucial to transforme thymic progenitors and to maintain their growth upon transformation, our study highlights a novel metabolic vulnerability with therapeutic potential for a high-risk T-ALL subgroup. Keywords: Acute lymphoblastic leukemia
P1532: CLINICAL OUTCOMES OF COVID-19 IN MYCOSIS FUNGOIDES AND SEZARY SYNDROME (MF/SS)
Authors: Ilana Levy, Lior Rokach, Guy Melamed, Hilel Alapi, Sivan Gazit, Tal Patalon, Tamar Tadmor
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Between 2020 and 2022, COVID-19 affected more than 70% of the Israeli population. It is now well known that haemato-oncologic patients are more susceptible to severe infections, including persistent COVID, and have a lower immune-response to COVID-19 vaccines than the general population. However, there is limited research on the outcomes of COVID-19 infection among patients with primary cutaneous lymphomas, such as Mycosis Fungoides and Sezary Syndrome (MF/SS). Aims: We aimed to assess the clinical outcomes of COVID-19 among patients with MF/SS during the period of 2020-2022. Methods: The data was retrieved from anonymized electronic medical records of Maccabi Healthcare Services, the second largest healthcare organization in Israel, after receiving approval from the institute’s ethical committee. Patients diagnosed with MF/SS by dermatologists, hematologists, or plastic surgeons and coded according to the ICD-9 system were included in the study. COVID-19 PCR test results, socio-demographic and clinical data were extracted and analyzed. Correlations tests and multivariate analyses were used to evaluate the association between COVID-19 infection, different COVID-19 variants, treatment, vaccination status, and clinical outcomes. Results: A total of 1472 patients diagnosed with MF/SS between 2020 and 2022 were included in the study. Among them, 768 (52%) had at least one confirmed SARS-CoV-2 infection by a PCR test, which was more prevalent among younger patients (p<0.001) and patients with comorbidities such as hypertension (p=0.009), overweight (p=0.001), kidney failure (p=0.046), osteoporosis (p=0.003) or dementia (p=0.046). The hospitalization rate was 2.9%, and the 30-day mortality rate from any cause after COVID-19 infection was 1.2% during the study period. Delta had the highest hospitalization rate (7.7%), among the three main COVID-19 variants, followed by Alpha (2.4%) and then Omicron (2.0%). During the Delta and Omicron surges, the hospitalization rate was lower among fully vaccinated patients, compared to non-vaccinated or non-fully vaccinated (p=0.032). However, it was higher among patients older than 65 (p<0.001) and patients with SS (vs. MF) (p<0.001) or COPD (p=0.024) diagnosis. Since January 2, 2022, the first day Nirmatrelvir was available for Maccabi patients, nirmatrelvir + ritonavir was administrated to 76 (11%) patients. There was a tendency for decreased hospitalization among patients treated within five days of infection, with a 79% risk reduction, although it was not statistically significant (p=0.164). Summary/Conclusion: It seems that patients with MF/SS do not necessarily have worse COVID-19 outcomes compared to the general population. However, further studies are needed to evaluate the effects of the different MF/SS treatments on COVID-19 severity and antibody formation to vaccination.Keywords: Mycosis fungoides, COVID-19